4-acetyl(1,2-a)pyrimido-(1,4)-benzo-diazepines

ABSTRACT

NOVEL 1H - 1,4 - BENZODIAZEPINE BEARING BETWEEN THE 1,2-POSITIONS A 5- OR 6-MEMBERED HERETOCYCLIC RING POSSESSING TWO NITROGEN ATOMS ARE DISCLOSED. THESE 1,2-HETEROCYCLIC-1H-1,4-BENZODIAZEPINES ARE USEFUL AS MUSCLE RELAXANT, ANTI-CONVULSANT AND SEDATIVE AGENTS.

United States Patent Ofice,

3,796,713 Patented Mar. 12, 1974 3,796,713 4-ACETYL[1,2-a]PYRlMlD0-(1,4)-BENZO- DIAZEPINES Michael Edward Derieg, Caldwell, Rodney Ian Fryer, North Caldwell, and Leo Henryk Sternbach, Upper Montclair, NJ., assignors to Hotlmann-La Roche Inc., Nutley, NJ. No Drawing. Filed Dec. 20, 1971, Ser. No. 210,253

Int. Cl. C07d 51/42 US. Cl. 260256.4 F 3 Claims ABSTRACT OF THE DISCLOSURE Novel 1H 1,4 benzodiazepine derivatives bearing between the 1,2-positions a 5- or 6-membered heterocyclic ring possessing two nitrogen atoms are disclosed. These l,2-heterocyclic-1l-I-1,4-benzodiazepines are useful as muscle relaxant, anti-convulsant and sedative agents.

DETAILED DESCRIPTION OF THE INVENTION wherein A is selected from the group consisting of n is the integer 0 or 1; R and R are selected from the group consisting of halogen, hydrogen, trifluoromethyl, nitro, lower alkyl, and cyano; R -R are each selected from the group consisting of hydrogen and lower alkyl; R signifies lower alkyl and R is selected from the group consisting of pyridyl, phenyl or halophenyl.

As used herein, the term lower alkyl refers to straight and branched chain hydrocarbon groups containing from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl, butyl and the like. The term halogen" refers to all four forms thereof, i.e., bromine, chlorine, fluorine and iodine. When the R substituent is pyridyl, the Z-pyridyl group is preferred. When the R substituent is a halophenyl group, the a-halophenyl group is preferred.

A preferred class of compounds falling within the scope of Formula I above are those wherein R signifies nitro or halogen, preferably chlorine, and is located in the 7- position of the basic benzodiazepine molecule, R is hydrogen, A is the group wherein R is phenyl or halophenyl, i.e., compounds of the formula wherein R is nitro or halogen, preferably chlorine; R is hydrogen or halogen, preferably chlorine or fluorine;

20 n and R3-"R7 are as described above.

Another preferred class of compounds falling within the scope of Formula I above are those wherein R is nitro or halogen, preferably chlorine, and is located in the 7-position of the basic benzodiazepine molecule, R R

are hydrogen, and A is the group I Ra wherein 1R is phenyl or halophenyl, i.e., compounds of the formula f t H20 CH| NCO-R1 R1 czN wherein R R ,'R and n are as described above.

The most preferred compounds of Formula I above are:

3-acetyl-'8-chloro-6-(Z-fluorophenyl)-2,3-dihydro-1H- imidazo[ 1,2-a] 1,4] benzodiazepine;

4-acetyl-9-chloro-7-(2-fluorophenyl)-1,2,3,4-tetrahydropyrimido(1,2-a) (1,4)benzodiazepine;

4-acetyl-9'-chloro-l,2,3,4-tetrahydro-7-phenylpyrimido 1,2-a) 1,4) benzodiazepine.

The compounds of Formula I above may be prepared by reacting a compound of the formula wherein R -R A and n are as described above with an acid anhydride of a carboxylic acid having from 2-5 carbon atoms.

Examples of acid anhydrides that can,be employedin the preparation of the desired end products of Formula I include acetic anhydride, propionic anhydride, butyric anhydride and the like.

The reaction between the compound of Formula II and the acid anhydride may be effected in the presence of an inert organic solvent; suitable solvents for this purpose include aromatic hydrocarbons such as benzene, toluene and the like, chlorinated hydrocarbons such as chloroform, methylene chloride and the like, and dimethylformamide (DMF). When the A substituent in the starting material of Formula II is a group, R defined as above, the reaction between this Formula II compound and the acid anhydride can be conducted at a temperature in the range of from about C. to the reflux temperature of the reaction medium. If in the starting material of Formula II the A substituent is a l J. Rs 0 group, R defined as above, then the reaction can be conducted at a temperature in the range of about 0 C. to room temperature. In either case, the reaction between the Formula 11 compound and the acid anhydride is preferably conducted at room temperature. Pressure is not critical to this reaction and thus for the sake of convenience the reaction is effected at atmospheric pressure.

The starting materials of Formula 11 above are known compounds or can be prepared in analogy to the preparation of the known compounds.

The compounds of Formula I above are useful as anticonvulsants, muscle relaxants and sedatives. Thus these compounds can be used as medicaments. For example, they can be used in the form of pharmaceutical preparations which contain them in admixture with a pharmaceutical, organic or inorganic carrier material which is suitable for enteral or parenteral application such as, for example, gelatin, lactose, starches, magnesium stearate, talc, vegetable oils, gum arabic, polyal-kylene glycols, Vaseline, etc. The pharmaceutical preparations can be prepared in solid form (e.g., as tablets, drages, suppositories, capsules) or in liquid form (e.g., as solutions, suspensions or emulsions). They can also contain other therapeutically valuable substances.

The compounds of Formula I above can be administered at dosages adjusted to individual requirements and fitted to the pharmaceutical exigencies of the situation. Convenient pharmaceutical dosages are in the range of from about 2 mg. to about 200 mg. per day.

The useful anti-convulsant activity of the compounds of this invention is shown in warm-blooded animals utilizing the standard antirnetrazole test. In the antimetrazole test, a compound is administered orally to groups of four mice at various dose levels. One hour later, .m'etrazole is administered subcutaneously and the animals are observed for protection from convulsive seizures. Results are recorded as the number of animals protected against convulsions. The dose at which 50% of the animals are protected from convulsive seizes is expressed as the ED Following these test procedures, compounds such as 4 acetyl 9 chloro-1,2,3,4-tetrahydro-7-phenylpyrimido- (1,2-a)(1,4)benzodiazepine and 3-acetyl-8-chloro-6-(2- afluorophenyl) 2,3 dihydro 1H imidazo[1,2 a] [1,4] benzodiazepine show an ED of 93.0:!:6.74 and 3.1:03 mg./kg. respectively, indicating that these compounds exhibit anticonvulsant activity.

The sedative and muscle relaxant activity of the compounds of the invention is shown using the standard foot shock test. In this test, a pair of mice is confined under a one liter beaker placed on a grid which presents shock to the feet. At least 5 fighting episodes are elicited in a 2-minute period. Pairs of mice are marked and pretreated 1 hour prior to a second shocking. Logarithmic dose intervals are utilized up to a maximum of 10 mg./kg. At the 100 percent blocking dose 3 out of 3 pairs must be blocked from fighting. The measurements are made at the dose level at which 100% blocking is observed and the results are expressed as the dose in mg./kg. which block the fighting response for one hour. Following these test procedures, 4-acetyl-9-chloro-7-(2-fluorophenyl) l,2,3,4- tetrahydropyrimido 1,2-a] 1,4] benzodiazepine exhibited a PD of 20 mg./kg. and 3-acetyl-8-chloro-6-(2-fluorophenyl)-2,3-dihydro-1H-imidazo[1,2 a] [1,4] benzodiazepine exhibited a PD of 10 mg./ kg.

The following examples are illustrative of the present invention. All temperatures given are in degrees centigrade.

EXAMPLE 1 Preparation of 3-acetyl-8-chloro-6- (2-fiuorophenyl)-2,3- dihydro-1H-imidazo[1,2-a] [1,4] benzodiazepine A solution of 1 g. (3.2 mmol) of 8-chloro-6-(2-fluorophenyl)-1,2-dihydro 4H imidazo[1,2-a][1,4]benzodiazepine 'in 10 ml. of acetic anhydride Was stirred for 2 hours at room temperature. The red precipitate was separated by filtration and the damp solid was stored over night under reduced pressure to remove the solvent. The above-named product was obtained as a red crystalline solid, M.P. 166-169".

EXAMPLE 2 Preparation of 4-acetyl-9-chloro-1,2,3,4-tetrahydro-7- phenylpyrimido[ 1,2-a] 1,4]benz0diazepine A solution of 25 ml. of acetic anhydride and 5.0 (16.1 mmol) of 9 chloro 1,2,3,5 tetrahydro 7 phenylpyrido[3,2-a] [1,4] benzodiazepine was stirred for 15 minutes by which time a bright orange solid had formed. The above-named product was obtained by filtration in crystalline form, M.P. 211-215". Recrystallization from chloroform/hexane gave orange prisms, M.P. 224-225 EXAMPLE 3 Preparation of 4-acetyl-9-chloro-7-(2-fiuorophenyl)-l,2, 3,4-tetrahydropyrimido[1,2-a] [1,4]benzodiazepine A solution of 5 ml. of acetic anhydride and 0.5 g. (1.5 mmol) of 9-chloro-7-(2-fluorophenyl) 1,2,3,5 tetrahydropyrimido[1,2-a][1,4]benzodiazepine was stirred for minutes and the above-named product was removed as an orange solid by filtration. Recrystallization from ether/ hexane gave orange prisms, M.P. 188190.

EXAMPLE 4 4-acetyl-9-chlor0-7-(2-fiuorophenyl)-1,2,3,4-tetrahydropyrimido(1,2-a) 1,4) benzodiazepine SUPPOSITORY FORMULATION Per 1.3 gm. suppository, gm.

4-acetyl 9 chloro-7-(2-fiuorophenyl) 1,2,3,4-

tetrahydropyrirnido(l,2-a)(1,4)benzodiazepine 0.010 Wecobee M 1 1.245 Carnauba wax 0.045

E. 13. Drew Company, 522 5th Avenue, New York, NY.

Procedure (1) The Wecobee M and the carnauba wax were melted in a suitable size glass-lined container (stainless steel may also be used), mixed well and cooled to 45 C.

(2) The 4-acetyl-9-chloro-7-(2 fiuorophenyl) 1,2,3, 4-tetrahydropyrimido(1,2 a)(l,4)benz0diazepine which has been reduced to a fine powder with no lumps, was added and stirred until completely and uniformly dispersed.

5 (3) The mixture was poured into suppository molds to yield suppositories having an individual weight of 1.3 grams.

(4) The suppositories were cooled and removed from molds. They were then individually wrapped in wax paper for packaging (foil may also be used).

EXAMPLE 5 4-acetyl-9-chloro-7-(Z-fiuorophenyl)-1,2,3,4-tetrahydro pyrimido( 1,2-a) 1,4) benzodiazepine CAPSULE FORMULATION Per capsule, mg. 4-acetyl 9 chloro 7 (2 fiuorophenyl)-1,2,34-

tetrahydropyrimido(1,2-a) (1,4)benzdiazepine 10 Lactose, U.S.P. 165 Corn starch, U.S.P. 30 Talc, U.S.P.

Total weight 210 Procedure 1) 4-acetyl 9 chloro-7-(2 fluorophenyl)-1,2,3,4- tetrahydr0pyrimido(1,2 a)(1,4)benzodiazepine, lactose and corn starch were mixed in a suitable manner.

(2) The mixture was further blended by passing through a Fitzpatrick Comminuting Machine with a #1A screen with knives forward.

(3) The blended powder was returned to the mixer, the tale added and blended thoroughly.

(4) The mixture was filled into #4 hard shell gelatin capsules on a Parke Davis capsulating machine. (Any similar type capsulating machine may be used.)

EXAMPLE 6 4-acety1-9-ch1oro-7-(Z-fluorophenyl)-1,2,3,4-tetrahydropyrimido 1,2-a) 1,4) benzodiazepine TABLET FORMULATION Per tablet, mg. 4acety1 9 chloro-7-(2-fluorophenyl) 1,2,21,4-

tetrahydropyrimido( l,2-a) (1,4)benzodiazepine- 25.00

Dicalcium phosphate dihydrate, unmilled 175.00

Corn starch 24.00

Magnesium stearate 1.00

Total weight 225.00

Procedure 1) 4-acetyl 9 chloro-7-(2-fiuorophenyl) 1,2,3,4- tetrahydropyrimido(1,2-a)(1,4)benzodiazepine and corn starch were mixed together and passed through a #00 screen in Model J Fitzmill with hammers forward.

N O 0lower alkyl halogenwherein R -R are each hydrogen; R is hydrogen or halogen; and lower alkyl is alkyl of one to four carbon atoms.

2. The compound of claim 1 wherein the halogen group is chlorine, R R are hydrogen, the lower alkyl group is methyl, i.e., 4-acetyl-9-chloro-1,2,3,4-tetrahydro- 7-phenylpyrimido (1,2-a) (1,4) -benzodiazepine.

3. The compound of claim 1 wherein the halogen group is chlorine, R R are hydrogen, the lower alkyl group is methyl, i.e. 4-acetyl-9-chloro-7-(2-fluoro-phenyl) 1,2,3, 4-tetrahydropyrimido (1,2-a) (1,4) -benzodiazepine.

References Cited UNITED STATES PATENTS 3,734,912 5/1973 Hanze 260256.5 R 3,651,046 3/1972 Derieg et a1. 260-2393 OTHER REFERENCES Derieg et al.: J. Med. Chem., 1968, 11(4), 912-13 (Eng.).

Chemical Abstract, 69:36092V (1968). Derieg et al.: Chem. Abstracts 70z87862Z (1969).

DONALD G. DAUS, Primary Examiner R. D. MCCLOUD, Assistant Examiner U.S. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent Nb. 3,196,713 Dated 3/12/74 I fl Michael E, Derieg; Rodney I. Fryer and Leo H. Sternbach It is certified that error appears in the above-identified patent and that said Letters Patentare herebycorrected as shown below:

Page 1, colunin l of Letters Patent The title l-Acetyl [l,2-a]Pyrimido (l, 4) Benzodiazepines" should be -4Acetyl (l ,2-a)Pyrimido(l,4) -Benzodiazepines Signed and sealed this 22nd day of April 1975.

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C MARSHALL DANN- ."-"1"T. 2'4: I" Rut. C 1 Cormnlssloner of Patents ttest1ng ri -leer and Trademarks USCOMM-DC 60376-P69 u.s. aovsnuuzm' PRINTING OFFICE Ion c-als-su,

FORM PO-105O (10-69) 

